Total synthesis and biological evaluation of potent analogues of dictyostatin: modification of the C2-C6 dienoate region.
By exploiting a Still-Gennari olefination of a common C11-C26 aldehyde with a C4-C10 or C1-C10 beta-ketophosphonate, three modified C2-C6 region analogues of the 22-membered macrolide dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the Taxol-resistant NCI/ADR-Res cell line. 6-Desmethyldictyostatin and 2,3-dihydrodictyostatin displayed potent (low nanomolar) antiproliferative activity, intermediate between dictyostatin and discodermolide, while 2,3,4,5-tetrahydrodictyostatin showed activity comparable to discodermolide. As with dictyostatin, these simplified analogues act through a mechanism of microtubule stabilisation, G2/M arrest and apoptosis.
Paterson
Ian
I
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK. ip100@cam.ac.uk
Gardner
Nicola M
NM
Guzmán
Esther
E
Wright
Amy E
AE
D000473:Alkanes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D018942:Macrolides; D011753:Pyrones; D014404:Tubulin; C470814:dictyostatin; C071229:discodermolide; D017239:Paclitaxel